22-19961490-C-T

Position:

• chr22-19961490-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000754.4(COMT):​c.-1+201C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 152,130 control chromosomes in the GnomAD database, including 19,053 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (19053 hom., cov: 35)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.438

Genes affected

COMT (HGNC:2228): (catechol-O-methyltransferase) Catechol-O-methyltransferase catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters dopamine, epinephrine, and norepinephrine. This O-methylation results in one of the major degradative pathways of the catecholamine transmitters. In addition to its role in the metabolism of endogenous substances, COMT is important in the metabolism of catechol drugs used in the treatment of hypertension, asthma, and Parkinson disease. COMT is found in two forms in tissues, a soluble form (S-COMT) and a membrane-bound form (MB-COMT). The differences between S-COMT and MB-COMT reside within the N-termini. Several transcript variants are formed through the use of alternative translation initiation sites and promoters. [provided by RefSeq, Sep 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COMT	NM_000754.4	c.-1+201C>T		intron_variant		ENST00000361682.11
COMT	NM_001135161.2	c.-1+201C>T		intron_variant
COMT	NM_001135162.2	c.-1+201C>T		intron_variant
COMT	NM_001362828.2	c.-295+201C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COMT	ENST00000361682.11	c.-1+201C>T		intron_variant		1	NM_000754.4	P2

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75692 AN: 152010 Hom.: 19047 Cov.: 35

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.468

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.498 AC: 75723 AN: 152130 Hom.: 19053 Cov.: 35 AF XY: 0.495 AC XY: 36798 AN XY: 74382

Gnomad4 AFR AF: 0.509

Gnomad4 AMR AF: 0.427

Gnomad4 ASJ AF: 0.460

Gnomad4 EAS AF: 0.268

Gnomad4 SAS AF: 0.456

Gnomad4 FIN AF: 0.551

Gnomad4 NFE AF: 0.520

Gnomad4 OTH AF: 0.465

Alfa AF: 0.504 Hom.: 24981

Bravo AF: 0.488

Asia WGS AF: 0.358 AC: 1246 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.6
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs165722; hg19: chr22-19949013;